PROJECT SUMMARY Traumatic brain injury (TBI) is a major clinical problem, as it causes enormous personal suffering and has far reaching economic implications. No pharmacological agent is currently approved for specific treatment of acute TBI. AivoCode, Inc., is developing a new approach to TBI therapy by using a novel peptide, AC1, which possesses a drug-like activity. AC1 when given as repeated intravenous injections during the first days after TBI strongly reduces the size of a brain lesion. Moreover, preliminary results suggest that there is also some functional improvement after AC1 treatment not seen in the controls, particularly in motor functions. Thus, AC1 is potentially useful in limiting the secondary damage in TBI. In this Phase I application, we propose to understand the processes that underlie this therapeutic effect and confirm the therapeutic and functional improvement in a more robust clinically relevant mouse model of severe TBI. Neuroimaging by MRI and a battery of established behavioral tests will be used to accomplish this goal. The potential for clinical translation of this approach is high, because the peptide has already been shown to strongly accumulate in brain lesions and reduce the size of the lesion by several criteria, and because it also recognizes human brain injury. Our study addresses an underserved medical area, where there is a pressing need for novel therapeutic advances.